This is the second renewal of this Program Project Grant, which has focused on the structure and function of key proteins in lipoprotein metabolism and atherosclerosis. During the next 5 years, our goals will be: 1) To identify the structural domains of apolipoproteins that regulate lipid transport; 2) To contribute to the understanding of the involvement of apo-B-containing lipoproteins in atherogenesis; and 3) To more fully understand the physiologic roles of lipoproteins and apolipoproteins in metabolism, including the roles of lipoproteins in embryonic development and in cardiac physiology. Four projects and four cores have been assembled, which interact closely and contribute significantly to each other. The research program is multi- disciplinary and relies on state-of-the-art technology, including X-ray crystallography, transgenic and gene-targeted mouse models, cellular biology, and ultrastructural biology. "Influence of Apolipoprotein E structure on Function," uses X-ray crystallography and biochemical approaches to determine the three- dimensional structure of apo-E and to determine how the three-dimensional structure affects lipoprotein metabolism. "Cellular Mechanism for Lipoprotein Retention in the Artery Wall," will test the hypothesis that proteoglycan binding sites in apo-B play a crucial role in the retention of lipoproteins in the artery wall and the development of atherosclerosis. "Alpha-TTP and Vitamin E in Development and Disease," explores the role alpha-tocopherol transfer protein and vitamin E in metabolism and atherosclerosis. The Cores (Animal Model; Histology, Atherosclerosis, Ultrastructure; Cell Culture and Protein Production; Administration) will provide the common services that are necessary for accomplishing the goals of the Program Project.